title: Autocrine production of IL-1 beta by human osteoarthritis-affected cartilage and differential regulation of endogenous nitric oxide, IL-6, prostaglandin E2, and IL-8.
abstract: Interleukin-1 beta (IL-1 beta) plays a central role in the pathophysiology of cartilage damage and degradation in arthritis. In noninflammatory arthropathies such as osteoarthritis (OA), the synovial-derived IL-1 beta has been implicated in the disease process. In this study, we report that human OA-affected cartilage demonstrates upregulated IL-1 beta mRNA not seen in normal cartilage. The OA-affected cartilage in ex vivo conditions spontaneously releases detectable amounts of autocrine IL-1 beta, nitric oxide (NO), and prostaglandin E2 (PGE2), known to be involved in cartilage damage and inflammation, that cannot be detected in normal cartilage. The autocrine IL-1 beta released by the OA-affected cartilage (for at least 72 hr in ex vivo conditions) is present in sufficient quantities to modulate NO and PGE2 production because addition of recombinant soluble IL-1 beta receptor (but not soluble tumor necrosis factor-alpha receptor) and cytokine-suppressive antiinflammatory drugs (CSAIDs) significantly attenuates the spontaneous release of NO and PGE2. Furthermore, OA-affected cartilage releases significant amounts of IL-6 and IL-8 in ex vivo conditions. Addition of CSAIDs to OA-affected cartilage differentially regulates IL-6 and IL-8 production by inhibiting the spontaneous release of IL-6 but not IL-8 in ex vivo conditions. These experiments demonstrate that the human OA-affected cartilage itself releases sufficient amounts of functionally active autocrine IL-1 beta that can modulate endogenous NO, PGE2, and IL-6, but not IL-8, all of which are known to be stimulated by IL-1 beta in vitro. These IL-1 beta induced pleotropic inflammatory mediators in OA-affected cartilage may be sufficient to facilitate or augment cartilage degradation and inhibit cartilage repair, and therefore lead the cartilage into an autodestructive pathway in osteoarthritis.
authors.affiliation: Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Attur
authors.forename: I R
authors.initials: IR
authors.lastname: Patel
authors.forename: R N
authors.initials: RN
authors.lastname: Patel
authors.forename: S B
authors.initials: SB
authors.lastname: Abramson
authors.forename: A R
authors.initials: AR
authors.lastname: Amin
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D017942:Nitric Acid / Q000378:metabolism*; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011725:Pyridines; D017942:Nitric Acid; D015232:Dinoprostone; C093642:SB 203580